JPS6258349B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to benzylidene derivatives, their production methods, and their pharmaceutical applications. Various benzylidene derivatives are described in Japanese Patent Application No. 51-92246 and Japanese Patent Application No. 54-22471 filed by the present applicant. The compound according to the present invention has the formula (): [Wherein, R is a linear or branched C _3-6 alkyl group or a C _2-6 alkenyl group, X ₁ is a halogen atom or a methyl group, X ₂ is a hydrogen atom or a methyl group, and X ₃ is a halogen Atom or methyl group, X ₄
represents a hydrogen atom, a chlorine atom or a methyl group] Among the compounds according to the present invention, preferred are R
is an alkyl group having 3 to 6 carbon atoms. Further, it is preferable that X ₂ is a hydrogen atom and X ₄ is at the 4' position. The compound () of the present invention can be produced according to the following reaction formula. Compounds of formula () are described in the aforementioned patent applications. The compounds of formula () are used in base or hydrochloride form. Compounds of formula () are described in the literature. The above reaction is carried out in an alcoholic solvent such as methanol or ethanol at a temperature of 10° C. to the boiling point of the solvent in the presence of an alkali metal or alkali metal alcoholate. Examples of the present invention are listed below. The structure of the product was confirmed by IR and NMR spectra. Example 1 2-[Butylimino-(2-chlorophenyl)-
Methyl]-4-chlorophenol [X ₁ = 4-Cl, X ₂ = H, X ₃ = 2-Cl, X ₄ =
H, R=n- _C4H9 ] 1,5 _- chloro-2-hydroxyphenyl-(2
-Chlorophenyl)-methanone A mixture of o-chlorobenzoic acid (313.14 g), thionyl chloride (600 ml) and pyridine (0.5 ml) is heated under reflux for 6 hours. Next, the operation of distilling off excess thionyl chloride, adding 250 ml of benzene and distilling it off is repeated twice. In this way o-chlorobenzoyl chloride is obtained. 257.12 g of p-chlorophenol, 2 methylene chloride and 280 ml of triethylamine are placed in 10 reaction vessels. The o-chlorobenzoyl chloride obtained above is dissolved in 1 part of methylene chloride and this is added over 2 hours. The reaction mixture is heated to reflux for 12 hours and left for 48 hours. Add 3 parts of water and make the mixture 10 parts
Stir for min, decant the organic phase and wash with water, add MgSO ₄
Dry with. The mixture is filtered and the liquid is evaporated to dryness to give an oil. When this oil is dissolved in 1 part petroleum ether and the solution is cooled, an ester of the following formula crystallizes: This is filtered, air-dried, and then dried at 50°C. 250 g of this ester are heated with 250 g of aluminum chloride. After hydrolysis, the obtained compound () was extracted with chloroform and the extract was dissolved in _MgSO4
Dry, filter, and evaporate to dryness. Recrystallization from petroleum ether, air drying, and drying in a desiccator yields the ketone with a melting point of 107.9°C. 2,2-[butylimino-(2-chlorophenyl)
-Methyl]-4-chlorophenol 7 g of the ketone obtained above are dissolved in 200 ml of ethanol, placed in a 500 ml round bottom flask, and 2 times 25 ml of n-butylamine are added. Stir the mixture until the ketone is completely no longer visible. The solution is evaporated to dryness and the residue is taken up in chloroform. The chloroform phase is washed several times with water, separated and dried over MgSO ₄ . Filter through a frit and evaporate to dryness. The product is crystallized from petroleum ether and the crystals are air dried on a frit and then in a desiccator. The melting point of the product obtained is 49.6°C. In another experiment, the melting point was 57.2℃ (result of differential thermal analysis)
of the compound was obtained in the same yield. This product is the same as the previous one, so there may be two different crystalline forms of this compound. Example 2 2-[Butylimino-(2,4-dimethylphenyl)-methyl]-4-methylphenol [ _X1 = 4-CH3, _X2 = H _{, X3} = 2- _CH3 , _X4
=4- _CH3 , R=n- _{C4H9 ]} As shown in the reaction formula below, 2-hydroxy-5 is produced by the method described in the above patent application specification.
-Methylphenyl-(2,4-dimethylphenyl)-methanone is used. Dissolve 6.25 g of the ketone obtained above in 200 ml of methanol and place in a 500 ml round bottom flask. Add 75 ml of n-butylamine and carry out the same reaction as in Example 1. The resulting compound is oily. Compounds according to the invention prepared according to the method of the Examples are shown in Table 1 below. For oily compounds, the refractive index (n ²³ _D ) is shown. Note that Table 1 also shows the results of pharmacological experiments described below.

【table】

[Table] When the compound according to the present invention was subjected to pharmacological experiments, it was found to have activity on the central nervous system. Acute toxicity was measured in mice after intraperitoneal administration. LD ₅₀ (50%) that kills 50% of the animals
The lethal dose) is 1000 for all compounds of the present invention.
mg/Kg or more. The pharmacological activity of this compound was evaluated using mice.
The antagonistic effect on mortality due to bicuculline administration was determined. Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors, and its convulsive and lethal activity is directed against compounds that increase central GABA concentrations or have GABA-like activity. Therefore, they are antagonistic. The 50% effective dose (AD ₅₀ ) of the test compound, i.e. the amount of compound that protects 50% of the animals from the effects of bicuculline, was determined as follows: for each test compound.
At least 10 animals were used and 0.90 mg/Kg of bicuculline in physiological serum solution was administered intravenously over 10 seconds (dose: 10 ml/Kg). 30 minutes after bicuculline administration,
The compounds of the present invention are prepared as a fine suspension in distilled water containing 1% Tween 80, or as a solution in distilled water.
It was administered intraperitoneally at a dose of 10ml/Kg. Three hours after bicuculline or test compound administration, the number of dead animals in each test group was counted. The AD ₅₀ of the compounds of the present invention measured in this manner is shown in Table 1 above. These results revealed that the compound of the present invention is effective as an anticonvulsant. These compounds are also effective in treating a variety of central nervous system diseases in humans and animals, including certain neurological disorders such as psychosis and epilepsy. Therefore, the present invention contains a compound represented by the general formula as an active ingredient and is suitable for administration, particularly oral administration (e.g. tablets, sugar-coated tablets, sugar-coated pills, capsules, casseroles, drinkable solutions or suspensions, etc.) or non-prescription drugs. Also included are anticonvulsants containing excipients suitable for oral administration. The daily dosage can be about 100 to 1500 mg. Formulation Example The following ingredients were mixed well in the indicated ratios, tableted, and coated with Pharmacoat 606 in a conventional manner to give 200% and 200% of Compound 1 of the present invention, respectively.
Tablets containing 300 and 400 mg are obtained.

【table】

[Table] Coating agent
Pharmacort 606 7mg 8mg 10mg

Claims (1)

[Claims] 1 Formula: [Wherein, R is a linear or branched C _3-6 alkyl group or a C _2-6 alkenyl group, X ₁ is a halogen atom or a methyl group, X ₂ is a hydrogen atom or a methyl group, and X ₃ is a halogen Atom or methyl group, X ₄
represents a hydrogen atom, a chlorine atom, or a methyl group] A compound represented by the following. 2. The compound according to item 1, wherein R is an alkyl group having 3 to 6 carbon atoms. 3. The compound according to item 1 or 2, wherein X ₂ is a hydrogen atom and X ₄ is at the 4' position. 4 2-[butylimino-(2-chlorophenyl)
-Methyl]-4-chlorophenol. 5. Compound according to paragraph 1 having the name 2-[butylimino-(2,4-dimethylphenyl)-methyl]-4,6-dimethylphenol. 6 Formula: [Wherein, R is a linear or branched C _3-6 alkyl group or a C _2-6 alkenyl group, X ₁ is a halogen atom or a methyl group, X ₂ is a hydrogen atom or a methyl group, and X ₃ is a halogen Atom or methyl group, X ₄
represents a hydrogen atom, a chlorine atom, or a methyl group] A method for producing a compound represented by the formula: A method characterized in that a ketone of the formula: is reacted with a compound of the formula: _RNH2 . 7 Formula: [Wherein, R is a linear or branched C _3-6 alkyl group or a C _2-6 alkenyl group, X ₁ is a halogen atom or a methyl group, X ₂ is a hydrogen atom or a methyl group, and X ₃ is a halogen Atom or methyl group, X ₄
represents a hydrogen atom, a chlorine atom, or a methyl group] An anticonvulsant agent containing a compound represented by the following as an active ingredient.